Compelling epidemiological evidence shows a strong positive correlation of obesity with thyroid cancer. In vivo studies have provided molecular evidence that high-fat-diet-induced obesity promotes thyroid cancer progression by aberrantly activating leptin-JAK2-STAT3 signaling in a mouse model of thyroid cancer (ThrbPV/PVPten+/- mice). The ThrbPV/PVPten+/- mouse expresses a dominantly negative thyroid hormone receptor beta (denoted as PV) and a deletion of one single allele of the Pten gene. The ThrbPV/PVPten+/- mouse spontaneously develops follicular thyroid cancer, which allows its use as a preclinical mouse model to test potential therapeutics. We recently showed that inhibition of STAT3 activity by a specific inhibitor markedly delays thyroid cancer progression in high-fat-diet-induced obese ThrbPV/PVPten+/- mice (HFD-ThrbPV/PVPten+/- mice). Further, metformin, a widely used antidiabetic drug, blocks invasion and metastasis, but not thyroid tumor growth in HFD-ThrbPV/PVPten+/- mice. To improve efficacy in reducing thyroid tumor growth, we treated HFD-ThrbPV/PVPten+/- with JQ1, a potent inhibitor of the activity of bromodomain and extraterminal domain (BET), and with metformin. We found that the combined treatment synergistically suppressed thyroid tumor growth by attenuating STAT3 and ERK signaling, resulting in decreased anti-apoptotic key regulators such as Mcl-1, Bcl-2, and sruvivin and increased pro-apoptotic regulators such as Bim, BAD and cleave caspase 3. Furthermore, combined treatment of JQ1 and metformin reduced cMYC protein levels to suppress vascular invasion, anaplasia, and lung metastasis. These findings indicate that combined treatment is more effective than metformin alone and suggest a novel treatment modality for obesity-activated thyroid cancer.